Lowering Glycosphingolipid Levels in CD4+ T Cells Attenuates T Cell Receptor Signaling, Cytokine Production, and Differentiation to the Th17 Lineage

Zhu, Yunxiang; Gumlaw, Nathan; Karman, Jozsef; Zhao, Hongmei; Zhang, Jinhua; Jiang, Ji Lei; Maniatis, Pete; Edling, Andrea E.; Chuang, Wei Lien; Siegel, Craig; Shayman, James A.; Kaplan, Johanne; Jiang, Canwen; Cheng, Seng H.

doi:10.1074/jbc.m111.218610

Cited by 48 publications

(37 citation statements)

References 39 publications

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“…Th17 cells have been suggested to contribute to neutrophilic, steroid-resistant severe asthma and to enhance Th2-mediated airway inflammation, although a role for the cells in asthma remains to be determined (41). Reportedly, GM3S null mice exhibit a decreased number of Th17 cells skewed by in vitro culture (42). Because the adoptive transfer experiments confirmed the marked reduction of allergic responses in WT mice that received a whole CD4 + T-cell population from sensitized GM3S null mice (Fig.…”

Section: Discussionmentioning

confidence: 60%

“…Concentrations of IL-2 and IFN-γ in culture supernatants were measured by ELISA as described elsewhere (45), using two types of anti-mouse IL-2 mAbs and anti-mouse IFN-γ mAb. Serum levels of OVA-specific IgE were measured with ELISA according to published methods (42). IL-4 and IL-5 contents in BAL fluid were measured using an ELISA kit (R&D Systems) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

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CD4 and CD8 T cells require different membrane gangliosides for activation

Nagafuku

Okuyama²,

Onimaru³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

118

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Initial events of T-cell activation involve movement of the T-cell receptor into lipid rafts. Gangliosides are major components of lipid rafts. While investigating T-cell activation in ganglioside-deficient mice, we observed that CD4 + and CD8 + T cells required different ganglioside subsets for activation. Activation of CD4 + T cells from GM3 synthase-null mice, deficient in GM3-derived gangliosides, is severely compromised, whereas CD8 + T-cell activation is normal. Conversely, in cells from GM2/GD2 synthase-null mice, expressing only GM3 and GD3, CD4 + T-cell activation is normal, whereas CD8 + T-cell activation is deficient. Supplementing the cells with the corresponding missing gangliosides restores normal activation. GM3 synthase-null mice do not develop experimental asthma. Distinct expression patterns of ganglioside species in CD4 + T and CD8 + T cells, perhaps in uniquely functional lipid rafts, define immune functions in each T-cell subset. Control of ganglioside expression would offer a strategy targeting for specific T-cell subpopulations to treat immune diseases.

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Section: Discussionmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

CD4 and CD8 T cells require different membrane gangliosides for activation

Nagafuku

Okuyama²,

Onimaru³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

118

View full text Add to dashboard Cite

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“…Moreover, recent reports show that CD4 + and CD8 + T cells exclusively require a-series and o-series GSLs, respectively, for TCR-mediated activation (8,36). The reduction of cellular GSL levels by pharmacological means or by disruption of GM3 synthase activity can inhibit the differentiation of CD4 + T cells into Th17 cells (7) and reduce cytokine production in activated T cells during viral infection (31).…”

Section: Discussionmentioning

confidence: 99%

“…The ability of inhibitors of GSL biosynthesis to restore defects in lipid (GSL and cholesterol) homeostasis and to inhibit T cell proliferation, cytokine production, and differentiation has been identified previously in cell lines and animal models (7,45). We found that NB-DNJ treatment of CD4 + T cells from patients with SLE modified their T cell function in response to in vitro TCR stimulation ( Figure 7).…”

Section: Measurement Of Gsl Traffickingmentioning

confidence: 99%

“…GSLs are enriched predominantly in lipid rafts, regions in the plasma membrane that coordinate the interaction of key signaling molecules that facilitate lymphocyte activation and function (2,5). Furthermore, differential GSL expression influences a range of T cell functions including TCR-mediated signaling (6)(7)(8), apoptosis (9), and recycling and endocytosis of membrane signaling and receptor molecules (4).…”

Section: Introductionmentioning

confidence: 99%

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Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

McDonald¹,

Deepak²,

Miguel³

et al. 2014

J. Clin. Invest.

135

128

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Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4 + T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4 + T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4 + T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4 + T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

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The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

et al. 2018

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Lipid rafts formed by glycosphingolipids (GSLs) on cellular membranes play important roles in innate and adaptive immunity. Lactosylceramide (LacCer) forms lipid rafts on plasma and granular membranes of human neutrophils. These LacCer‐enriched lipid rafts bind directly to pathogenic components, such as pathogenic fungi‐derived β‐glucan and Mycobacteria‐derived lipoarabinomannan via carbohydrate‐carbohydrate interactions, and mediate innate immune responses to these pathogens. In contrast, a‐series and o‐series gangliosides form distinct rafts on CD4+ and CD8+ T cell subsets, respectively, contributing to the respective functions of these cells and stimulating adaptive immune responses through T cell receptors. These findings suggest that gangliosides play indispensable roles in T cell selection and activation. This Review introduces the involvement of GSL‐enriched lipid rafts in innate and adaptive immunity.

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Lowering Glycosphingolipid Levels in CD4+ T Cells Attenuates T Cell Receptor Signaling, Cytokine Production, and Differentiation to the Th17 Lineage

Cited by 48 publications

References 39 publications

CD4 and CD8 T cells require different membrane gangliosides for activation

CD4 and CD8 T cells require different membrane gangliosides for activation

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

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